MerTK Inhibition Aggravates Pancreatic Inflammation and Structural Damage via the NF-κB Pathway in an in vivo Type 2...

Type 2 diabetes mellitus (T2DM) is characterized by chronic inflammation and progressive pancreatic β-cell dysfunction. The Mer receptor tyrosine kinase (MerTK) regulates immune homeostasis and inflammation, but its role in T2DM-related islet injury remains unclear. This study aimed to investigate the effects of MerTK and its inhibition on pancreatic structure, metabolic parameters, and NF-κB-mediated inflammation in a rat model of T2DM.

Seventy male Sprague-Dawley rats were randomized into five groups: normal control (CON), CON+MRX-2843 (MerTK inhibitor), T2DM 2-week (T2DM-2; assessed 2 weeks after diabetes induction), T2DM 12-week (T2DM-12; assessed 12 weeks after diabetes induction), and T2DM-12+MRX-2843. T2DM was induced by a high-fat/high-sugar diet plus streptozotocin injection. In the intervention groups, MRX-2843, a selective MerTK inhibitor (65 mg/kg/day) was administered by gavage for two weeks after successful diabetes induction, including after 10 weeks of diabetes exposure in the T2DM-12+MRX-2843 group. Serum MerTK, glucose, lipids, insulin, and pro-inflammatory cytokines (NF-κB, TNF-α, IL-1β) were measured by ELISA, and pancreatic histology was evaluated by HE staining.

Serum MerTK expression increased with diabetes duration, peaking in the T2DM-12 group (47.5% higher than CON). MerTK inhibition significantly reduced MerTK levels by 21.3% versus T2DM-12 but aggravated metabolic dysfunction, with higher fasting glucose (+13.3%), HbA1c (+2.5%), total cholesterol (+16.9%), triglycerides (+32.6%), and insulin (+8.5%) compared to non-inhibited T2DM rats. Pro-inflammatory cytokines were markedly elevated after MRX-2843 treatment, particularly NF-κB (+35.2%), TNF-α (+48.2%), and IL-1β (+70.3%) in the T2DM-12+MRX-2843 group. Histological analysis showed progressive islet atrophy and vacuolation with diabetes, which became more severe after MerTK inhibition, indicating enhanced structural damage.

MerTK expression is dynamically upregulated in T2DM and exerts a compensatory protective effect by limiting NF-κB-driven inflammation and preserving pancreatic integrity. Pharmacological inhibition of MerTK exacerbates cytokine release, metabolic disturbances, and pancreatic injury, suggesting that MerTK may represent a promising candidate for further therapeutic investigation in T2DM.